Multiple Myeloma
Conditions
Brief summary
The purpose of this study is to evaluate the clinical benefit of subcutaneous (SC) daratumumab administered in combination with standard multiple myeloma (MM) regimens in participants with MM as measured by overall response rate (ORR) or very good partial response (VGPR) or better rate.
Detailed description
The hypothesis is that the addition of daratumumab administered SC to standard MM regimens will improve responses compared to response data observed in completed phase 3 studies without daratumumab. Disease evaluations will include measurements of myeloma proteins, bone marrow examinations, skeletal surveys, assessment of extramedullary plasmacytomas, and measurements of serum calcium corrected for albumin. Safety will be measured by adverse events, laboratory test results, electrocardiogram (ECGs), vital sign measurements, physical examination findings, SC injection-site assessments, and assessment of Eastern Cooperative Oncology Group (ECOG) performance status score. Study will consist of 3 phases (screening, treatment and follow-up) and duration of study is approximately 3 years.
Interventions
DRUGDaratumumab
Daratumumab will be administered at a dose of 1800 mg by SC injection in Cycles 1 to 4 in D-VRd cohort and until documented progression of disease, unacceptable toxicity, or end of study for D-VMP, D-Rd and D-Kd cohorts.
DRUGBortezomib
Bortezomib will be administered as 1.3 mg/m\^2 SC injection in Cycles 1 to 4 in D-VRd cohort and in Cycles 1 to 9 in D-VMP cohort.
DRUGLenalidomide
Lenalidomide will be administered as 25 mg capsule orally in Cycles 1 to 4 in D-VRd cohort and in all Cycles until documented progression of disease, unacceptable toxicity, or end of study in D-Rd cohort.
DRUGDexamethasone
Dexamethasone will be administered as 20 mg orally or intravenously in Cycles 1 to 4 in D-VRd cohort; 40 mg orally or intravenously in all cycles and thereafter until documented progression of disease, unacceptable toxicity, or end of study in D-Rd and D-Kd cohort.
DRUGMelphalan
Melphalan will be administered as 9 mg/m\^2 orally in Cycles 1 to 9.
DRUGPrednisone
Prednisone will be administered as 60 mg/m\^2 orally in cycles 1 to 9.
DRUGCarfilzomib
Carfilzomib will be administered as 20 mg/m\^2 IV on Day 1 of Cycle 1 only then 70 mg/m\^2 IV on Days 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2 and thereafter until documented progression of disease, unacceptable toxicity, or end of study in D-Kd cohort.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Multiple myeloma diagnosed according to the International Myeloma Working Group (IMWG) diagnostic criteria * Measurable, secretory disease as defined by any of the following: 1. Serum monoclonal paraprotein (M-protein) level greater than or equal to (\>=) 1.0 gram per deciliter (g/dL); or 2. Urine M-protein level \>= 200 milligram per 24 hours (mg/24 hours); or 3. Light chain multiple myeloma (MM), for participants without measurable disease in the serum or urine: serum Immunoglobulin (Ig) free light chain (FLC) \>= 10 mg/dL and abnormal FLC ratio * Meets one of the sets of the following criteria: 1. For Daratumumab + bortezomib + lenalidomide + dexamethasone (D-VRd) and Daratumumab + bortezomib + melphalan + prednisone + dexamethasone (D-VMP) regimen: newly diagnosed myeloma 2. For Daratumumab + lenalidomide + dexamethasone (D-Rd) and Daratumumab + Carfilzomib + Dexamethasone (D-Kd) regimen: relapsed or refractory disease 3. D-Kd cohort: Participants must have received only 1 prior line of therapy for MM which included at least 2 consecutive cycles of lenalidomide therapy * Eastern Cooperative Oncology Group (ECOG) Performance Status grade of 0, 1, or 2 * During the study, during dose interruptions, and for 3 months after receiving the last dose of any component of the study treatment, a female participant must agree not to donate eggs (ova, oocytes) and male participants of reproductive potential must not donate semen or sperm during the study, during dose interruptions, or for 3 months after the last dose of any study drug
Exclusion criteria
* History of malignancy (other than MM) unless all treatment of that malignancy was completed at least 2 years before consent and the participant has no evidence of disease further exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or breast, or other non-invasive lesion, that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years * Exhibits clinical signs of meningeal involvement of MM * Either of the following: a) Chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) is less than (\<) 50 percentage (%) of predicted normal b) Moderate or severe persistent asthma, or a history of asthma within the last 2 years, or currently has uncontrolled asthma of any classification c) For D-Kd cohort: Known infiltrative pulmonary disease or known pulmonary hypertension * Any of the following: a) Known to be seropositive for human immunodeficiency virus; b) Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen \[HBsAg\]). Participants with resolved infection (participants who are HBsAg negative but positive for antibodies to hepatitis B core antigen \[Anti-HBc\] and/or antibodies to hepatitis B surface antigen \[Anti-HBs\]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are polymerase chain reaction (PCR) positive will be excluded * Known to be seropositive for hepatitis C (Anti-HCV antibody positive or HCV-RNA quantitation positive) except in the setting of a sustained virologic response \[SVR\], defined as aviremia at least 12 weeks after completion of antiviral therapy * For D-Kd cohort only: Transthoracic echocardiogram showing left ventricular ejection fraction (LVEF) \<40%; uncontrolled hypertension, defined as an average systolic blood pressure greater than (\>)159 millimeters of mercury (mmHg) or diastolic \>99 mmHg despite optimal treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| D-VMP, D-Rd, and D-Kd Cohorts: Overall Response Rate (ORR) | Up to 2 years 3 months | ORR was defined as the percentage of participants who achieved partial response (PR) or better according to international myeloma working group (IMWG) criteria. IMWG criteria for PR: greater than or equal to (\>=) 50 percent (%) reduction of serum M-protein and reduction in 24-hour urinary M-protein by \>=90% or to less than (\<) 200 milligrams (mg) per 24 hours, If the serum and urine M-protein are not measurable, a decrease of \>=50% in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, \>=50% reduction in bone marrow plasma cells (PCs) is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \>=30%. In addition to the above criteria, if present at baseline, a \>=50% reduction in the size of soft tissue plasmacytomas is also required. |
| D-VRd Cohort: Percentage of Participants With Very Good Partial Response (VGPR) or Better Response | Up to 2 years and 3 months | VGPR or better rate was defined as the percentage of participants who achieved VGPR or complete response (CR) (including stringent complete response \[sCR\]) according to the IMWG criteria during or after the study treatment. VGPR: Serum and urine component detectable by immunofixation but not on electrophoresis, or \>= 90% reduction in serum M-protein plus urine M-protein level \<100 mg/24 hour; CR: negative immunofixation on the serum and urine, Disappearance of any soft tissue plasmacytomas and \<5% PCs in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by immunohistochemistry, immunofluorescence, 2-4 color flow cytometry. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| D-VMP, D-Rd, and D-Kd Cohorts: Percentage of Participants With VGPR or Better Response | From baseline up to 2 years 7 months | VGPR or better rate was defined as the percentage of participants who achieved VGPR or CR (including sCR) according to the IMWG criteria during or after the study treatment. VGPR: Serum and urine component detectable by immunofixation but not on electrophoresis, or \>= 90% reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hour; CR: negative immunofixation on the serum and urine, Disappearance of any soft tissue plasmacytomas and \<5% PCs in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by immunohistochemistry, immunofluorescence, 2-4 color flow cytometry. |
| D-VRd Cohort: Overall Response Rate (ORR) | Up to 2 years and 3 months | ORR was defined as the percentage of participants who achieved a PR or better, IMWG criteria, during the study or during follow up. IMWG criteria for PR \>= 50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by \>=90% or to \<200 mg/24 hours, if the serum and urine M-protein are not measurable, a decrease of \>=50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, \>=50% reduction in bone marrow PCs is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \>=30%, in addition to the above criteria, if present at baseline, a \>=50% reduction in the size of soft tissue plasmacytomas is also required. |
| Percentage of Participants With CR or Better Response | For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months | CR or better rate was defined as the percentage of participants with a CR or better response (that is, CR and sCR) as per IMWG criteria. CR: as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and less than (\<) 5 percent plasma cells in bone marrow; sCR: CR plus normal FLC ratio and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry. |
| Maximum Observed Serum Concentration (Cmax) of Daratumumab | D-VRd: Day 4 of Cycles 1 and 4 and post treatment at Week 8; D-VMP: Day 4 of Cycles 1 and 2 and post treatment at Week 8; D-Rd and D-Kd: Day 4 of Cycles 1 and 3 and post treatment at Week 8 | Cmax was defined as maximum serum concentration observed following daratumumab administration. Each cycle for: D-VRd cohort is of 21 days, D-VMP cohort is of 42 days and D-Rd and D-Kd cohorts is of 28 days. Each cohort have a treatment period of 84 days. |
| Percentage of Participants With Anti-Daratumumab Antibodies | For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months | Percentage of participants with antibodies to daratumumab were reported. |
| Percentage of Participants With Anti-rHuPH20 Antibodies | For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months | Percentage of participants with antibodies to rHuPH20 were reported. |
| D-VMP, D-Rd, and D-Kd Cohorts: Percentage of Participants With Minimal Residual Disease (MRD) Negative Rate | Up to 2 years and 3 months | MRD negativity rate was defined as the percentage of participants who were considered MRD negative after MRD testing at any timepoint after the first dose by bone marrow aspirate. MRD negativity rate was assessed by next-generation sequencing at a threshold of \<10\^5. |
| D-VMP, D-Rd and D-Kd Cohorts: Duration of Response (DOR) | From baseline up to 2 years 7 months | DOR was defined as the time from the date of initial documented response (PR or better response) to the date of first documented evidence of progressive disease (PD) or death due to PD. PD is defined as an increase of 25% from the lowest response value in one of the following: serum and urine M-component (absolute increase must be \>=0.5 gram per deciliter \[g/dL\] and \>=200 mg/24 hours respectively); only in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels (absolute increase must be \>10 mg/dL); definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that can be attributed solely to PC proliferative disorder. |
| Percentage of Participants With Infusion-Related Reactions (IRRs) | For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months | Percentage of Participants with IRRs were reported. The administration-related systemic reactions are referred to as IRRs. |
Countries
Brazil, Czechia, France, Germany, Israel, Japan, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Daratumumab (D)+Bortezomib+Lenalidomide+Dexamethasone (D-VRd) Participants received daratumumab 1800 milligrams (mg) as a subcutaneous (SC) injection on Days 1, 8 and 15 of Cycles 1 to 3 (each cycle of 21 days) and on Day 1 of Cycle 4; bortezomib 1.3 milligrams per square meter (mg/m\^2) SC injection on Days 1, 4, 8 and 11 of Cycles 1 to 4; lenalidomide 25 mg orally on Day 1 through Day 14 of Cycles 1 to 4 and dexamethasone 20 mg orally or intravenously (IV) on Days 1, 2 ,8, 9, 15 and 16 of Cycle 1 to 4. | 67 |
| D + Bortezomib + Melphalan + Prednisone (D-VMP) Participants received daratumumab 1800 mg by SC injection on Days 1, 8, 15, 22, 29 and 36 of Cycle 1, then on Days 1 and 22 in Cycles 2 to 9, and Day 1 of Cycle 10 and thereafter until documented progression of disease, unacceptable toxicity, or up to 2 years and 7 months; bortezomib 1.3 mg/m\^2 SC injection on Day 1, 4, 8, 11, 22, 25, 29 and 32 of Cycle 1 and on Days 1, 8, 22 and 29 of Cycles 2 to 9; melphalan 9 mg/m\^2 orally on Day 1 through Day 4 of Cycles 1 to 9; prednisone 60 mg/m\^2 orally on Days 1 to 4 of cycles 1 to 9. | 67 |
| Daratumumab + Lenalidomide + Dexamethasone (D-Rd) Participants received daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2, then on Day 1 and 15 of Cycles 3 to 6, and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or up to 2 years and 7 months; lenalidomide 25 mg orally on Day 1 through Day 21 of each cycle until documented progression of disease, unacceptable toxicity, or end of study and dexamethasone 40 mg orally or intravenously weekly until documented progression of disease, unacceptable toxicity, or up to 2 years and 7 months. | 65 |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) Participants received daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2 (each cycle is of 28 days), then on Day 1 and 15 of Cycles 3 to 6, and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or up to 2 years and 7 months; Carfilzomib 20 mg/m\^2 IV on Day 1 of Cycle 1 only, then 70 mg/m\^2 IV on Days 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2 and thereafter until documented progression of disease, unacceptable toxicity, or up to 2 years and 7 months and dexamethasone 40 mg orally or IV weekly for Cycles 1-9, then on Days 1, 8, 15 of each cycle for Cycle 10 and thereafter until documented progression of disease, unacceptable toxicity, or up to 2 years and 7 months. | 66 |
| Total | 265 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Data collection ended | 0 | 41 | 41 | 40 |
| Overall Study | Death | 1 | 3 | 4 | 5 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 4 | 5 | 5 |
Baseline characteristics
| Characteristic | D + Bortezomib + Melphalan + Prednisone (D-VMP) | Daratumumab + Lenalidomide + Dexamethasone (D-Rd) | Daratumumab (D)+Bortezomib+Lenalidomide+Dexamethasone (D-VRd) | Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 74.9 years STANDARD_DEVIATION 4.54 | 66.8 years STANDARD_DEVIATION 9.58 | 57.3 years STANDARD_DEVIATION 9.47 | 61 years STANDARD_DEVIATION 9.77 | 65 years STANDARD_DEVIATION 10.87 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 0 Participants | 3 Participants | 7 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 45 Participants | 34 Participants | 43 Participants | 161 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 22 Participants | 20 Participants | 30 Participants | 16 Participants | 88 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 5 Participants | 2 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 15 Participants | 18 Participants | 24 Participants | 16 Participants | 73 Participants |
| Race (NIH/OMB) White | 46 Participants | 45 Participants | 38 Participants | 48 Participants | 177 Participants |
| Region of Enrollment BRAZIL | 4 Participants | 0 Participants | 1 Participants | 0 Participants | 5 Participants |
| Region of Enrollment CZECH REPUBLIC | 4 Participants | 15 Participants | 4 Participants | 0 Participants | 23 Participants |
| Region of Enrollment FRANCE | 21 Participants | 17 Participants | 26 Participants | 15 Participants | 79 Participants |
| Region of Enrollment GERMANY | 0 Participants | 0 Participants | 0 Participants | 19 Participants | 19 Participants |
| Region of Enrollment ISRAEL | 7 Participants | 14 Participants | 0 Participants | 0 Participants | 21 Participants |
| Region of Enrollment JAPAN | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
| Region of Enrollment SPAIN | 19 Participants | 0 Participants | 11 Participants | 25 Participants | 55 Participants |
| Region of Enrollment UNITED KINGDOM | 8 Participants | 12 Participants | 9 Participants | 0 Participants | 29 Participants |
| Region of Enrollment UNITED STATES | 0 Participants | 7 Participants | 16 Participants | 7 Participants | 30 Participants |
| Sex: Female, Male Female | 36 Participants | 20 Participants | 19 Participants | 32 Participants | 107 Participants |
| Sex: Female, Male Male | 31 Participants | 45 Participants | 48 Participants | 34 Participants | 158 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 67 | 3 / 67 | 4 / 65 | 5 / 66 |
| other Total, other adverse events | 67 / 67 | 67 / 67 | 65 / 65 | 66 / 66 |
| serious Total, serious adverse events | 19 / 67 | 30 / 67 | 37 / 65 | 22 / 66 |
Outcome results
Primary
D-VMP, D-Rd, and D-Kd Cohorts: Overall Response Rate (ORR)
ORR was defined as the percentage of participants who achieved partial response (PR) or better according to international myeloma working group (IMWG) criteria. IMWG criteria for PR: greater than or equal to (\>=) 50 percent (%) reduction of serum M-protein and reduction in 24-hour urinary M-protein by \>=90% or to less than (\<) 200 milligrams (mg) per 24 hours, If the serum and urine M-protein are not measurable, a decrease of \>=50% in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, \>=50% reduction in bone marrow plasma cells (PCs) is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \>=30%. In addition to the above criteria, if present at baseline, a \>=50% reduction in the size of soft tissue plasmacytomas is also required.
Time frame: Up to 2 years 3 months
Population: All treated analysis set included all participants who have received at least 1 dose of study treatment. This primary outcome measure (OM) was planned to be analyzed for D-VMP, D-Rd and D-Kd cohorts only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D + Bortezomib + Melphalan + Prednisone (D-VMP) | D-VMP, D-Rd, and D-Kd Cohorts: Overall Response Rate (ORR) | 88.1 percentage of participants |
| Daratumumab + Lenalidomide + Dexamethasone (D-Rd) | D-VMP, D-Rd, and D-Kd Cohorts: Overall Response Rate (ORR) | 90.8 percentage of participants |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | D-VMP, D-Rd, and D-Kd Cohorts: Overall Response Rate (ORR) | 84.8 percentage of participants |
Primary
D-VRd Cohort: Percentage of Participants With Very Good Partial Response (VGPR) or Better Response
VGPR or better rate was defined as the percentage of participants who achieved VGPR or complete response (CR) (including stringent complete response \[sCR\]) according to the IMWG criteria during or after the study treatment. VGPR: Serum and urine component detectable by immunofixation but not on electrophoresis, or \>= 90% reduction in serum M-protein plus urine M-protein level \<100 mg/24 hour; CR: negative immunofixation on the serum and urine, Disappearance of any soft tissue plasmacytomas and \<5% PCs in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by immunohistochemistry, immunofluorescence, 2-4 color flow cytometry.
Time frame: Up to 2 years and 3 months
Population: All treated analysis set included all participants who have received at least 1 dose of study treatment. This primary outcome measure (OM) was planned to be analyzed for D-VRd cohort only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D + Bortezomib + Melphalan + Prednisone (D-VMP) | D-VRd Cohort: Percentage of Participants With Very Good Partial Response (VGPR) or Better Response | 71.6 percentage of participants |
Secondary
D-VMP, D-Rd and D-Kd Cohorts: Duration of Response (DOR)
DOR was defined as the time from the date of initial documented response (PR or better response) to the date of first documented evidence of progressive disease (PD) or death due to PD. PD is defined as an increase of 25% from the lowest response value in one of the following: serum and urine M-component (absolute increase must be \>=0.5 gram per deciliter \[g/dL\] and \>=200 mg/24 hours respectively); only in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels (absolute increase must be \>10 mg/dL); definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that can be attributed solely to PC proliferative disorder.
Time frame: From baseline up to 2 years 7 months
Population: Analysis population included number of responders (partial response or better) in each cohort. This secondary outcome measure was planned to be analyzed for D-VMP, D-Rd and D-Kd cohorts.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| D + Bortezomib + Melphalan + Prednisone (D-VMP) | D-VMP, D-Rd and D-Kd Cohorts: Duration of Response (DOR) | NA months |
| Daratumumab + Lenalidomide + Dexamethasone (D-Rd) | D-VMP, D-Rd and D-Kd Cohorts: Duration of Response (DOR) | NA months |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | D-VMP, D-Rd and D-Kd Cohorts: Duration of Response (DOR) | NA months |
Secondary
D-VMP, D-Rd, and D-Kd Cohorts: Percentage of Participants With Minimal Residual Disease (MRD) Negative Rate
MRD negativity rate was defined as the percentage of participants who were considered MRD negative after MRD testing at any timepoint after the first dose by bone marrow aspirate. MRD negativity rate was assessed by next-generation sequencing at a threshold of \<10\^5.
Time frame: Up to 2 years and 3 months
Population: All treated analysis set included all participants who have received at least 1 dose of study treatment. This secondary OM was planned to be analyzed for D-VMP, D-Rd and D-Kd cohorts only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D + Bortezomib + Melphalan + Prednisone (D-VMP) | D-VMP, D-Rd, and D-Kd Cohorts: Percentage of Participants With Minimal Residual Disease (MRD) Negative Rate | 25.4 percentage of participants |
| Daratumumab + Lenalidomide + Dexamethasone (D-Rd) | D-VMP, D-Rd, and D-Kd Cohorts: Percentage of Participants With Minimal Residual Disease (MRD) Negative Rate | 21.5 percentage of participants |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | D-VMP, D-Rd, and D-Kd Cohorts: Percentage of Participants With Minimal Residual Disease (MRD) Negative Rate | 27.3 percentage of participants |
Secondary
D-VMP, D-Rd, and D-Kd Cohorts: Percentage of Participants With VGPR or Better Response
VGPR or better rate was defined as the percentage of participants who achieved VGPR or CR (including sCR) according to the IMWG criteria during or after the study treatment. VGPR: Serum and urine component detectable by immunofixation but not on electrophoresis, or \>= 90% reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hour; CR: negative immunofixation on the serum and urine, Disappearance of any soft tissue plasmacytomas and \<5% PCs in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by immunohistochemistry, immunofluorescence, 2-4 color flow cytometry.
Time frame: From baseline up to 2 years 7 months
Population: All treated analysis set included all participants who have received at least 1 dose of study treatment. This secondary OM was planned to be analyzed for D-VMP, D-Rd and D-Kd cohorts only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D + Bortezomib + Melphalan + Prednisone (D-VMP) | D-VMP, D-Rd, and D-Kd Cohorts: Percentage of Participants With VGPR or Better Response | 77.6 percentage of participants |
| Daratumumab + Lenalidomide + Dexamethasone (D-Rd) | D-VMP, D-Rd, and D-Kd Cohorts: Percentage of Participants With VGPR or Better Response | 80.0 percentage of participants |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | D-VMP, D-Rd, and D-Kd Cohorts: Percentage of Participants With VGPR or Better Response | 77.3 percentage of participants |
Secondary
D-VRd Cohort: Overall Response Rate (ORR)
ORR was defined as the percentage of participants who achieved a PR or better, IMWG criteria, during the study or during follow up. IMWG criteria for PR \>= 50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by \>=90% or to \<200 mg/24 hours, if the serum and urine M-protein are not measurable, a decrease of \>=50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, \>=50% reduction in bone marrow PCs is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \>=30%, in addition to the above criteria, if present at baseline, a \>=50% reduction in the size of soft tissue plasmacytomas is also required.
Time frame: Up to 2 years and 3 months
Population: All treated analysis set included all participants who have received at least 1 dose of study treatment. This secondary OM was planned to be analyzed for D-VRd cohort only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D + Bortezomib + Melphalan + Prednisone (D-VMP) | D-VRd Cohort: Overall Response Rate (ORR) | 97.0 percentage of participants |
Secondary
Maximum Observed Serum Concentration (Cmax) of Daratumumab
Cmax was defined as maximum serum concentration observed following daratumumab administration. Each cycle for: D-VRd cohort is of 21 days, D-VMP cohort is of 42 days and D-Rd and D-Kd cohorts is of 28 days. Each cohort have a treatment period of 84 days.
Time frame: D-VRd: Day 4 of Cycles 1 and 4 and post treatment at Week 8; D-VMP: Day 4 of Cycles 1 and 2 and post treatment at Week 8; D-Rd and D-Kd: Day 4 of Cycles 1 and 3 and post treatment at Week 8
Population: Pharmacokinetics (PK) analysis set: participants who received at least 1 dose of daratumumab SC and had at least 1 PK sample value after first dose. 'N' (number of participants analyzed): participants evaluated for this OM; 'n' (number analyzed): participants analyzed at specific timepoints. The 0 in the number analyzed field indicates that no participant was evaluable for PK at that timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| D + Bortezomib + Melphalan + Prednisone (D-VMP) | Maximum Observed Serum Concentration (Cmax) of Daratumumab | Post-treatment Phase Week 8 | 263 micrograms per milliliter (mcg/mL) | Standard Deviation 190 |
| D + Bortezomib + Melphalan + Prednisone (D-VMP) | Maximum Observed Serum Concentration (Cmax) of Daratumumab | Cycle 4 Day 4 | 746 micrograms per milliliter (mcg/mL) | Standard Deviation 275 |
| D + Bortezomib + Melphalan + Prednisone (D-VMP) | Maximum Observed Serum Concentration (Cmax) of Daratumumab | Cycle 1 Day 4 | 100 micrograms per milliliter (mcg/mL) | Standard Deviation 48.5 |
| Daratumumab + Lenalidomide + Dexamethasone (D-Rd) | Maximum Observed Serum Concentration (Cmax) of Daratumumab | Post-treatment Phase Week 8 | 162 micrograms per milliliter (mcg/mL) | — |
| Daratumumab + Lenalidomide + Dexamethasone (D-Rd) | Maximum Observed Serum Concentration (Cmax) of Daratumumab | Cycle 2 Day 4 | 612 micrograms per milliliter (mcg/mL) | Standard Deviation 256 |
| Daratumumab + Lenalidomide + Dexamethasone (D-Rd) | Maximum Observed Serum Concentration (Cmax) of Daratumumab | Cycle 1 Day 4 | 98.6 micrograms per milliliter (mcg/mL) | Standard Deviation 51.6 |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | Maximum Observed Serum Concentration (Cmax) of Daratumumab | Cycle 3 Day 4 | 648 micrograms per milliliter (mcg/mL) | Standard Deviation 238 |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | Maximum Observed Serum Concentration (Cmax) of Daratumumab | Cycle 1 Day 4 | 108 micrograms per milliliter (mcg/mL) | Standard Deviation 49.9 |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | Maximum Observed Serum Concentration (Cmax) of Daratumumab | Cycle 3 Day 4 | 869 micrograms per milliliter (mcg/mL) | Standard Deviation 274 |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | Maximum Observed Serum Concentration (Cmax) of Daratumumab | Cycle 1 Day 4 | 137 micrograms per milliliter (mcg/mL) | Standard Deviation 56.7 |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | Maximum Observed Serum Concentration (Cmax) of Daratumumab | Post-treatment Phase Week 8 | 49.3 micrograms per milliliter (mcg/mL) | Standard Deviation 109 |
Secondary
Percentage of Participants With Anti-Daratumumab Antibodies
Percentage of participants with antibodies to daratumumab were reported.
Time frame: For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months
Population: Immunogenicity-evaluable analysis set was defined as all participants who received at least 1 dose administration of daratumumab SC and had at least 1 immunogenicity sample for detection of anti-daratumumab antibodies after the first dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D + Bortezomib + Melphalan + Prednisone (D-VMP) | Percentage of Participants With Anti-Daratumumab Antibodies | 0 percentage of participants |
| Daratumumab + Lenalidomide + Dexamethasone (D-Rd) | Percentage of Participants With Anti-Daratumumab Antibodies | 0 percentage of participants |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | Percentage of Participants With Anti-Daratumumab Antibodies | 0 percentage of participants |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | Percentage of Participants With Anti-Daratumumab Antibodies | 0 percentage of participants |
Secondary
Percentage of Participants With Anti-rHuPH20 Antibodies
Percentage of participants with antibodies to rHuPH20 were reported.
Time frame: For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months
Population: Immunogenicity-evaluable analysis set for rHuPH20 is defined as all participants who received at least one dose of daratumumab SC and had appropriate plasma samples for detection of antibodies to rHuPH20 (at least 1 sample after the start of the first dose of daratumumab SC).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D + Bortezomib + Melphalan + Prednisone (D-VMP) | Percentage of Participants With Anti-rHuPH20 Antibodies | 6.1 percentage of participants |
| Daratumumab + Lenalidomide + Dexamethasone (D-Rd) | Percentage of Participants With Anti-rHuPH20 Antibodies | 3.1 percentage of participants |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | Percentage of Participants With Anti-rHuPH20 Antibodies | 4.8 percentage of participants |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | Percentage of Participants With Anti-rHuPH20 Antibodies | 4.7 percentage of participants |
Secondary
Percentage of Participants With CR or Better Response
CR or better rate was defined as the percentage of participants with a CR or better response (that is, CR and sCR) as per IMWG criteria. CR: as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and less than (\<) 5 percent plasma cells in bone marrow; sCR: CR plus normal FLC ratio and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry.
Time frame: For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months
Population: All treated analysis set included all participants who have received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D + Bortezomib + Melphalan + Prednisone (D-VMP) | Percentage of Participants With CR or Better Response | 16.4 percentage of participants |
| Daratumumab + Lenalidomide + Dexamethasone (D-Rd) | Percentage of Participants With CR or Better Response | 55.2 percentage of participants |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | Percentage of Participants With CR or Better Response | 50.8 percentage of participants |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | Percentage of Participants With CR or Better Response | 42.4 percentage of participants |
Secondary
Percentage of Participants With Infusion-Related Reactions (IRRs)
Percentage of Participants with IRRs were reported. The administration-related systemic reactions are referred to as IRRs.
Time frame: For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months
Population: All treated analysis set included all participants who have received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D + Bortezomib + Melphalan + Prednisone (D-VMP) | Percentage of Participants With Infusion-Related Reactions (IRRs) | 9.0 percentage of participants |
| Daratumumab + Lenalidomide + Dexamethasone (D-Rd) | Percentage of Participants With Infusion-Related Reactions (IRRs) | 9.0 percentage of participants |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | Percentage of Participants With Infusion-Related Reactions (IRRs) | 4.6 percentage of participants |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | Percentage of Participants With Infusion-Related Reactions (IRRs) | 4.5 percentage of participants |